Progress in elucidation of disease at the molecular level supports the idea that the development of novel pharmaceutical tools for manipulation of gene expression would open the door to new medical therapies. Even though major research efforts have lead to very significant advances in gene therapy, antisense, ribozymes, RNAi and related fields, practical applications of these technologies in medicine are still in very early stages. This is especially true with respect to gene-specific agonists (i.e. activators) that could provide a unique solution for difficult medical challenges such as cancer and sickle cell anemia. Our goal is to establish a new gene targeting technology based on synthetic analogs of eukaryotic transcription factors-artificial transcription factors (ATFs). Natural transcriptional activators have modular structure including these 2 crucial parts: a DNA-binding domain (DBD) and an activation domain (AD). The ATF concept is based on building DBDs and ADs from synthetic chemical moieties and combining them into molecules with novel, drug-like properties such as cell permeability and resistance to enzymatic degradation. In Phase I, we propose to develop a novel design for ATFs based on the small-molecule moiety that, by virtue of having an affinity for a key component of transcriptional apparatus, is able to function as an effective AD. The Specific aims of this proposal are: 1. To synthesize novel small-molecule containing ATFs. 2. To demonstrate the effectiveness of these ATFs in tissue-culture transcription assays. These aims will be accomplished by employing a combination of organic chemistry, automated synthesis and molecular biology techniques. The results of this Phase I research may have important implications in pharmaceutical drug development and may provide new tools for basic research in molecular genetics. [unreadable] [unreadable] [unreadable]